Acne is one of the most common conditions observed in the dermatology clinical practice. It affects nearly all adolescents and young adults to some extent. As suggested by Anthony Mancini, the effects of acne are not limited to skin—acne lesions among adolescents and young adults generally occur at the time of heightened emotional sensitivity and may contribute to significant psychological distress, depression, and even increased risk of suicide (Anthony Mancini; Incidence, prevalence, and pathophysiology of acne; Johns Hopkins Adv Stud Med, volume 8 (4), 100-105 (2008)).
Over the last approximately thirty years, minocycline has been one of the most widely prescribed oral antibiotic treatments for acne. It was first introduced in the US more than thirty years ago and has been available in different dosage forms such as capsules, tablets, lyophilized powder for injection, and suspension (now discontinued). Minocycline has also been formulated as an extended-release powder (PLGA microspheres) for the treatment of periodontal disease. In the UK, minocycline hydrochloride is also available as gel (Dentomycin™ gel) formulation for use in periodontal disease.
Minocycline has a unique biological activity profile: it has both antibacterial and anti-inflammatory properties. It was first launched as a broad spectrum antibiotic for a variety of infectious diseases. Beyond the antibacterial activity, minocycline also has been investigated for new indications, such as its use in neurologic diseases as a potential neuro-protective agent and in ophthalmic diseases. However, minocycline also has been associated with certain adverse effects, especially on prolonged use and at higher doses. Two recent review articles provide a comprehensive summary of minocycline's efficacy and adverse effects in the clinical use.
Leon Kircik (J of Drugs in Dermatology, November 2010) reviewed and compared efficacy and safety of minocycline and doxycycline in moderate-to-severe inflammatory acne patients.
Falk Ochsendorf (Minocycline in Acne Vulgaris—Benefits and Risks, Falk Ochsendorf, American J Clinical Dermatology, 2010) notes that compared with first-generation tetracyclines, minocycline has a better pharmacokinetic profile in man (with practically 100% oral bioavailability), and compared with doxycycline, it is not phototoxic. However, the author suggests that compared with other tetracyclines, minocycline has an increased risk of severe adverse effects: for example, it may induce hypersensitivity reactions affecting the liver, lung, kidneys, or multiple organs (Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS] syndrome) in the first weeks of treatment and, with long-term treatment, may cause autoimmune reactions (systemic lupus erythematosus, autoimmune hepatitis). In addition, CNS symptoms, such as dizziness, are reportedly more frequent with minocycline, as compared with other tetracyclines. Long-term treatment with minocycline may also induce hyper-pigmentation of the skin or other organs. Resistance of P. acnes to minocycline also occurs, depending on the prescribing behavior. The author concludes that, considering minocycline's efficacy (through oral administration), its adverse effect profile (from systemic exposure), resistance, price, and alternatives, it is no longer considered the first-line antibacterial in the treatment of acne.
It has been suggested that minocycline, upon repeated oral administration, accumulates in the skin structures and thus imparts its antibacterial and anti-inflammatory activities. Duration of treatment and dose are limited by the potential adverse effects, as described above. These adverse effects are, obviously, directly attributable to its systemic exposure. Systemic exposure is the dose and duration limiting factor in the treatment of acne.
For the treatment of acne, we have appreciated that it would be desirable to have a topical formulation of minocycline for the following reasons: first, it will afford targeted delivery of minocycline at the disease site where it is required and second, and more importantly, a topical administration will significantly reduce (or potentially eliminate) systemic exposure of minocycline. It would be reasonable to expect that lower minocycline systemic exposure would result in minimizing its adverse effects, enable potential for longer-term therapy (longer than 12-weeks that is currently prescribed with oral treatments), and reduce some of the contraindications currently associated with oral formulations.
There have not been any commercially successful topical formulations of minocycline for the treatment of acne reported yet. A major challenge in the development of the topical formulation of minocycline has been its chemical nature: it is unstable in solution form and is also sensitive to moisture, temperature, and light. The most commonly reported impurity is formed through the epimerization of minocycline at C-4 resulting in the formation of the 4-epi-minocycline stereoisomer of minocycline—a minocycline related substance listed in the US and European pharmacopeias with defined limits. The structures of 4-epiminocycline and minocycline are provided below:
Consequently, it has not been possible to formulate a topical formulation that contains minocycline in a stable solubilized form. Periodontal topical minocycline gel (Dentomycin gel; 1% minocycline gel, in clinical use in the UK) must be stored at refrigerated temperatures, presumably due to stability issues. Following is a brief description of related art in the field.
US patent application US 2008/0188446A1 (and references therein) succinctly describes prior art in the field and concludes that none of the past attempts have adequately addressed the stability of tetracycline and provided a stable topical formulation for this class of compounds. US2008/0188446A1 describes a formulation for minocycline and doxycycline incorporating cyclomethicone, ST-Elastomer 10 and isopropyl myristate. While this formulation might provide some stability to the API, it contains isopropyl myristate, a known comedogenic substance thus limiting its usefulness in the treatment of acne.
WO 2011/039637A2 and US patent application 2010/0310476A1 describe an elaborate method and complex constituents for foam formulation of tetracyclines. A foam formulation, as claimed in the above applications, whilst having some stability might not deliver a consistent amount of the active substance to the site of application over the duration of treatment. It also requires an extra layer of complexity for the delivery of drug formulation using a foam pump. Similarly, US 2011/0281827 A1 and US 2012/0087872 A1 require use of a pump to deliver a foam formulation.
US patent application 2012/0093876A1 describes suspension formulations of minocycline hydrochloride in oil and in petrolatum for ophthalmic use. It concludes that minocycline hydrochloride in an oil suspension is unstable after two months with change in color. However, a petrolatum based ointment suspension was considered stable enough for further investigation by these investigators. We have discovered that, surprisingly, minocycline can in fact be stabilized in an oil containing suspension, for example a suspension oil gel formulation (details of which are described more fully below) is quite stable at ambient temperatures for one year the stability testing was conducted.
We have appreciated there remains a medical need for a stable, practical, commercially feasible and easy to manufacture and easy to use topical formulation of tetracycline class of compounds, especially but not exclusively comprising minocycline and doxycycline, and particularly comprising minocycline, which formulation can be administered to a patient in need for the treatment of infections or inflammation and for the treatment of dermatologic, ophthalmic or neurological disease.